Figures

Abstract

Background

It is not known whether or not delivering acupuncture triggers mechanisms
cited as placebo and if acupuncture or sham reduces radiotherapy-induced
emesis more than standard care.

Methodology/Principal Findings

Cancer patients receiving radiotherapy over abdominal/pelvic regions were
randomized to verum (penetrating) acupuncture (n = 109;
99 provided data) in the alleged antiemetic acupuncture point PC6 or sham
acupuncture (n = 106; 101 provided data) performed with
a telescopic non-penetrating needle at a sham point 2–3 times/week
during the whole radiotherapy period. The acupuncture cohort was compared to
a reference cohort receiving standard care (n = 62; 62
provided data). The occurrence of emesis in each group was compared after a
mean dose of 27 Gray. Nausea and vomiting were experienced during the
preceding week by 37 and 8% in the verum acupuncture group, 38 and
7% in the sham acupuncture group and 63 and 15% in the
standard care group, respectively. The lower occurrence of nausea in the
acupuncture cohort (verum and sham) compared to patients receiving standard
care (37% versus 63%, relative risk (RR) 0.6, 95 %
confidence interval (CI) 0.5–0.8) was also true after adjustment for
potential confounding factors for nausea (RR 0.8, CI 0.6 to 0.9). Nausea
intensity was lower in the acupuncture cohort (78% no nausea,
13% a little, 8% moderate, 1% much) compared to the
standard care cohort (52% no nausea, 32% a little, 15%
moderate, 2% much) (p = 0.002). The acupuncture
cohort expected antiemetic effects from their treatment (95%).
Patients who expected nausea had increased risk for nausea compared to
patients who expected low risk for nausea (RR 1.6; Cl 1.2–2.4).

Conclusions/Significance

Patients treated with verum or sham acupuncture experienced less nausea and
vomiting compared to patients receiving standard care, possibly through a
general care effect or due to the high level of patient expectancy.

Funding: This study was supported by The Swedish Cancer Society, The Vardal Institute, The
County Council of Ostergotland, The University of Linköping, Cancer and
Traffic Injury Fund and The Vardal Foundation for Health Care Sciences and
Allergy Research. Mats Lekander and Martin Ingvar are members of Stockholm Brain
Institute funded by Vinnova and The Swedish Strategic Research Foundation. The
funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Many cancer patients express interest in acupuncture for nausea [1]-[2] but it is not known if acupuncture
is more effective for emesis (nausea and vomiting) than standard care during
radiotherapy. Approximately 60% of patients irradiated over abdominal and/or
pelvic fields experienced emesis during radiotherapy [1], [3]–[4]. Antiemetics are effective,
especially serotonin-receptor antagonists combined with corticosteroids [5]. However, some
patients at risk for nausea do not receive potent antiemetics, do not respond
satisfactorily [1], [3], [5], or experience side-effects [5]. In a previous study we found
that of 145 nauseous patients irradiated over a variety of regions, one third asked
for more treatment against nausea while 40% rejected antiemetics [1].

Between two and 31% of patients undergoing cancer treatment use acupuncture
for various kinds of symptoms [2]. In chemotherapy-induced nausea, acupuncture and
acupressure reduced nausea more than antiemetics, but those studies did not include
any sham treated control groups [6]–[11]. In a study of 80
chemotherapy patients, penetrating acupuncture did not reduce nausea more than
telescopic non-penetrating sham needles [12]. In our study of
radiotherapy-induced nausea, 70% of patients randomized to penetrating
acupuncture and 62% of patients treated with telescopic sham needles
experienced nausea during the radiotherapy period [13]. Apparently there was a lack of
effects that could be related to the specific characteristics of verum (genuine)
acupuncture; i.e. stimulation of skin penetrating needles in traditional acupuncture
points resulting in a “deqi” sensation. However, as many as 95%
of patients in both groups considered the treatment to be
effective, and 89% were interested in receiving the treatments in the future
[13]. In the
light of the apparent conflict between lack of specific effects from verum
acupuncture and large subjectively experienced positive effects it seems interesting
to evaluate if acupuncture has antiemetic effects related to nonspecific
mechanisms.

The aims of the study were to compare nausea and vomiting experienced by a cohort
treated with verum or sham acupuncture with that experienced by a cohort receiving
standard care during radiotherapy, and to evaluate if expectations of nausea and of
acupuncture effects were related to the actual occurrence of nausea.

Materials and Methods

The protocol for this trial and supporting CONSORT checklist are available as
supporting information; see Protocol S1 and Checklist
S1.

Inclusion

Two cohorts of patients treated for cancer in three Swedish oncology departments
were included: one a standard care and the other an acupuncture cohort, see
figure 1. The standard
care cohort was created by a cross-sectional selection in four different days at
two oncology departments in 1999 and 2003 [1]
(n = 62). The acupuncture cohort was created from
consecutively included patients in 2004 to 2006 at one of the two oncology
departments referred to above and also in another oncology department [13]. Members of
this cohort were randomized to verum acupuncture (n = 109)
or sham acupuncture (n = 106). Inclusion criteria for both
cohorts were that patients were at least 18 years of age, had radiotherapy over
abdominal or pelvic fields and were able to take part in the study procedure.
Exclusion criteria for the acupuncture cohort only were radiotherapy of less
than 800 cm3 volume and 25 Gray dose, antiemetic treatment or
persistent nausea within 24 hours prior to the start of radiotherapy and
acupuncture treatment during the past year for any indication or ever for
nausea.

All patients gave their informed written consent and the Regional Ethical Review
Board in Linköping, Sweden, approved the study. The informed consent form
used in the acupuncture cohort contained the information: “You will
receive an ordinary acupuncture treatment with needles penetrating the skin or
another treatment with needles placed just against the skin”. The
study-evaluator and all health-care professionals, with the exception of the
acupuncture-providing therapists, were blind to the acupuncture allocation. The
standard care group knew, of course, that no acupuncture was given. They had
been informed that the aim of the data collection was to evaluate the prevalence
of nausea during radiotherapy.

Treatment regimens

The acupuncture and the standard care cohort were, except for study
participation, treated according to clinical routines, including the use of
rescue antiemetics. The standard care cohort received no acupuncture therapy.
One physiotherapist at each hospital (performing 1412 and 607 treatments)
performed both verum and sham acupuncture and they had five deputy
physiotherapists (performing 228, 75, 54, 32 and 6 treatments). Treatments
started on the first day of radiotherapy, continued 30 minutes per session three
times/week for two weeks, and then twice/week, until the end of radiotherapy
according to a standardised treatment protocol. The patients were in a hotel,
ward unit or at the radiotherapy department during the treatments, received
either in a sitting or a supine position. The physiotherapists treated one to
three patients simultaneously and maintained an everyday conversation, but
avoided the subject of nausea.

Verum acupuncture was administered bilaterally to the
traditional antiemetic point pericardium six (PC6) [14] between the tendons of
palmaris longus and flexor carpii radialis at two body-inches proximal of the
wrist crease. Sharp needles, diameter 0.30 × length 40 millimetres, were
inserted into a depth of a half body-inch. One body-inch (or a
“cun”: approximate 1.5 cm) is equivalent to the greatest width of
the individual patient's thumb at the distal phalanx. The needles were
manipulated three times/treatment by twirling and lifting until
“deqi” occurred. “Deqi” is the specific sensation of
verum acupuncture, involving heaviness, numbness, soreness and a minimal
muscular contraction around the needle [15].

Sham acupuncture was administered bilaterally to a sham point
located two body-inches proximal to PC6, outside traditional acupuncture points.
“Park's sham devise” [16], 0.30×40 millimetres
(extended length) was used. The credible [13] blunt telescopic needle
glides upwards into its handle instead of penetrating the skin, and thus gives
the illusion of penetration. Double-sticky marking tubes, used in both groups,
held the sham needles in place. The therapists manipulated the sham needles
three times/session until the needles touched the skin, but no
“deqi” occurred. The duration of needle pressure to the skin was
approximately ten seconds/session.

Data collection

Background data.

Clinical data, listed in table
1, were extracted from the patients' medical records. Other
background variables, listed in table 2, were collected in a written
questionnaire.

Nausea, vomiting and use of antiemetics.

Type/dose of antiemetics and emesis during the previous 24-hours were
measured by written established emesis questions [1], [17]: “Have you
experienced nausea?”, answered on a four-level category scale:
“No, not at all” or “Yes, a little/moderate/much”
and “Have you been vomiting?” answered by “No” or
“Yes”. In the acupuncture cohort the questions were asked daily
during the whole radiotherapy period. In the standard care cohort, the
questions were asked only once (after a mean dose of 27 Gray of
radiotherapy) and at that time the questions were asked regarding the
previous 24 hours and also within the time frame of the preceding week.
Every patient who had experienced nausea at least once within the preceding
seven days (irrespective of intensity) or vomiting was assigned to the
groups “Experiencing nausea” or “Experiencing
vomiting”. The emesis questions showed in pilot studies satisfactory
face-validity (n = 9), construct validity
(Spearman's correlation coefficient (r) 1.0;
n = 456 paired observations) and test-retest
reliability (r 0.98–1.0; n = 36).

Expectations of treatment effects and on nausea.

At the end of the first, the sixth and the last verum or sham treatment the
physiotherapists asked the patients: “Do you believe that the
treatment that you have just received is effective in preventing or reducing
nausea?” The four answer categories were “No, I do not think the
treatment is effective” and “Yes, I believe a
little/moderately/much that the treatment is effective”. Before
treatment was started, the verum and sham treated patients answered the
written question: “In relation to others, how do you estimate your own
risk for becoming nauseous during the radiotherapy period?” to be
answered on a five-grade category scale from “Much lower risk”
to “Much higher risk”.

Statistical analysis

The acupuncture cohort was compared with the standard care cohort using
Student's t-test regarding continuous data, Mann Whitney U-test regarding
ordinal or continuous, not normally distributed, data and by Fisher's exact
(two categories), or Chi2-test (three categories or more), regarding category
data. Relative risk (RR) for nausea with 95% confidence intervals (CI)
was calculated for each of the different subgroups shown in table 1 and table 2 as compared to a
reference group (RR 1.0), defined as the subgroup with the lowest prevalence of
nausea. One exception was made; the subgroup of patients believing
“little” in antiemetic effects of verum/sham treatment was not
chosen as a reference group, because it consisted of only ten patients. A
multivariable logistic regression model was constructed to determine the
relative importance of the different characteristics seen in and table 2 1 for explaining the
occurrence of nausea (Logistic procedure, forward selection) and the RR for
nausea was adjusted in proc Genmod, with a log link and binomial error
distribution. At the time that both cohorts received a mean radiotherapy dose of
27 Gray the standard care cohort was compared with the acupuncture cohort
regarding occurrence of nausea and vomiting. SPSS for Windows (version 15.0.0)
was used, except for calculating adjusted RR risks for nausea where we used SAS
(version 9.1.3.). The significance level was set as p<0.05.

Results

Participants

Compared to the acupuncture cohort the standard care cohort comprised more men
(p = 0.02), more patients with a testicular tumour
(p = 0.001) and fewer patients consuming potent
antiemetics; serotonin-receptor antagonists (p = 0.09) or
corticosteroids (p<0.001) (table 1). According to the univariable analysis, nausea was not
related to gender (table
2) but was more frequent in patients with testicular tumours and in
patients treated with serotonin-receptor antagonists or corticosteroids (table 1). In the
multivariable analysis, concomitant chemotherapy (p = 0.01,
table 1), age less
than 40 years (p<0.001), previous nausea in any situation (p<0.001) and a
self estimated risk for nausea as higher than others during radiotherapy
(p = 0.01) all indicated a significantly increased risk for
nausea (table 2).

Emesis in the verum, sham and standard care group

The patients in the acupuncture cohort the past week and the past 24 hours
experienced significantly less occurrence of nausea and vomiting than those in
the standard care cohort. The lower occurrence of nausea in the acupuncture
cohort (37%) compared to the standard care cohort (63%) the past
week (RR 0.6, CI 0.45–0.77) was also true when patients taking
serotonin-receptor antagonists and corticosteroids were excluded (figure 2) and after adjustment
for confounding factors for nausea (table 3).

Figure 2. Nausea and vomiting within the past 24 hours and the past
week.

Emesis was measured at that time the radiotherapy dose was 27 Gray (mean)
in the verum, sham and standard care groups. Measured in all patients
and in patients not receiving potent antiemetics in the verum
(n = 88 and n = 77), sham
(n = 95 and n = 78) and
standard care group (n = 62 and
n = 55).

The intensity of nausea was lower in the acupuncture cohort (n 140; 78%
experienced no nausea, n = 24; 13% a little nausea,
n = 14; 8% moderate nausea and
n = 2; 1% much nausea) than in the standard care
cohort (n = 32; 52% no nausea,
n = 20; 32% a little, n 9; 15% moderate and n
1; 2% much) (p = 0.002). Within the acupuncture
cohort, no statistically significant differences between the verum and the sham
group were seen regarding nausea occurrence or intensity, vomiting or antiemetic
consumption the past 24 hours or the past week.

Expectations of nausea and the effects of treatment in the verum and sham
acupuncture groups

The 27 patients in the acupuncture cohort who estimated their own risk for
becoming nauseous during the radiotherapy as higher than other patients had an
increased risk for nausea compared to the 44 patients who estimated that they
had a lower risk for nausea than others (table 2). No statistically significant
differences in baseline expectations of antiemetic treatment effects were seen
between the patients who experienced nausea and the patients who stayed free
from nausea during the radiotherapy period (table 2). The patients who experienced nausea
between the sixth and last treatments either retained or decreased their
original belief in the antiemetic effects of the received treatment. The
patients who stayed free from nausea either retained their original belief that
the treatment would help or even reported an increase in the extent to which
they trusted this treatment (figure
3). Of the patients mostly treated by therapist A (performing 1412 of
1700 treatments, 83%), 20 of 69 (29%) in the verum acupuncture
group and 25 of 76 (33%) in the sham acupuncture group experienced nausea
the past week. In the patients mostly treated by therapist B (performing 607 of
693 treatments, 87%), corresponding figures were 13 of 41 (32%)
and 10 of 29 (35%), respectively.

Figure 3. Trust in the effect of the received treatment for preventing and
reducing nausea.

The trust was stated at the sixth and the last verum or sham treatment in
patients free from nausea and patients experiencing nausea after the
sixth verum or sham treatment. Number of patients rating trust in
antiemetic effects of received treatment at both the sixth and the last
session was 183.

Discussion

We found lower occurrence of nausea and vomiting in patients treated with penetrating
“deqi”-creating acupuncture or sham acupuncture compared to patients who
had received standard care. Almost all patients in the acupuncture cohort highly
expected antiemetic effects from the treatment. Patients who expected nausea had
increased risk for nausea compared to patients who expected low risk for nausea.

There are many, not sham-controlled studies, reporting emesis-reducing effects of
acupuncture compared to standard care in chemotherapy-induced nausea [14]. Our results
indicate that nonspecific factors such as the extra care or the high expectations of
positive treatment effects, not the specific characteristics of verum acupuncture,
reduced emesis. Alternatively, the findings could result from flaws in our
non-randomized design. Since the patients were not randomized to standard care, we
investigated if an imbalance of confounding factors possibly contributing to emesis
may have explained the higher prevalence of emesis in the standard care group,
according to the hierarchical step model [18]. The higher risk for nausea
in the standard care cohort was valid also after adjusting for possible confounding
factors for emesis and after omitting patients taking serotonin-receptor antagonists
and corticosteroids, indicating that our findings are valid. We have not identified
any previous study of the effect of verum or sham acupuncture compared to standard
care on radiotherapy-induced emesis (Pubmed, http://www.ncbi.nlm.nih.gov/ pubmed/accessed 10/11/10, using the
combined search terms acupuncture, radiotherapy, nausea and vomiting). A Cochrane
review of acupuncture for chemotherapy-induced nausea included
eleven studies [14].
Only two sham-controlled studies were reported, one positive
(n = 104) [19] and one negative (n = 80) [12], except
for a pilot study including only 10 patients [20]. As concerns conditions in
general, there exist positive sham controlled studies, but there are also
indications that the effect of acupuncture may not be related to the specific
characters of verum acupuncture. In line with our results, Haake and co-workers
[21] found
substantial improvement of back pain in 48% of 387 patients treated by verum
acupuncture, in 44% of 387 patients treated with sham and in 27% of
388 patients receiving standard care. In other studies sham acupuncture reduced
musculoskeletal arm pain significantly more than verum acupuncture [22].

The verum and the sham group received extra care compared to the standard care group,
which may have reduced emesis: patient-therapist communication, the knowledge that
continuous contact with one single therapist would continue during the whole
radiotherapy period, the tactile stimulation from the therapists' hands, the
extra time for rest and relaxation and the extra attention to the patient's
symptoms through the daily emesis questions all are important elements of this extra
care. The verum and sham performing therapists in our study might have had a
supportive attitude. Arving and co-workers [23] found that chemotherapy
patients who received supportive conversations reported higher quality of life and
less nausea than did patients receiving standard care. Börjeson and co-workers
[24] also
found that chemotherapy patients who received extra care comprising information and
relaxation training increased their well-being compared to patients receiving
antiemetics only, despite the fact that the extra-care group received a less optimal
antiemetic treatment.

Both verum acupuncture and sham-acupuncture like tactile stimulation have been seen
to activate the limbic system [15]; did the low dose of sensory stimulation at the
non-acupuncture point reduce emesis? Kaptchuk and co-workers [25] implied that the
patient-therapist meeting was more important than the needle stimulation. Of 87
patients who received sham acupuncture from an emphatic committed therapist
62% reported adequate symptom relief of irritable bowel symptoms, compared to
44% of 88 patients receiving sham acupuncture from a non-communicating
therapist and 28% of 87 patients on waiting list. The verum and sham treated
patients in our study received extra time for rest and relaxation and slightly more
body-contact than the standard care patients, which may have reduced distress.
Psychological distress has been seen as a predictor for emesis [26] and studies indicate that
relaxation [27]
as well as body-contact (tactile stimulation, massage) [28] may reduce nausea in cancer
patients.

Since almost all patients in the acupuncture cohort expected positive antiemetic
effects of the treatment, the positive expectation may be another factor that
reduced emesis. Expectations are known to influence intervention outcomes in general
[29]. Indeed,
Pariente and co-workers [30] found with the use of positron emission tomography (PET)
that when individuals were informed that the blunt sham needle they were treated
with was ineffective, no activity in the pain modulating areas in the mid-brain was
seen. When a credible telescopic sham needle was used that the individuals believed
was effective, a large pain-modulating activity was seen. Likewise, Linde and
co-workers [31]
found that acupuncture and sham treated patients with headache, chronic low back
pain or osteoarthritis who had high expectations on pain-reduction reported better
effects than patients with low expectations. In our study there were no differences
in the occurrence of nausea between the patients who believed in the antiemetic
effects of treatment and those who had a lesser belief in the antiemetic effects of
treatment. Either expectations about the treatment effect were not important for
nausea, or the category scale used was not sufficiently sensitive, thus resulting in
a “roof effect”. The patients' trust in the antiemetic effect of
verum or sham acupuncture decreased if nausea occurred and increased if nausea did
not occur. This finding is in concordance with results from experiments indicating
that the placebo response is a short-time effect; for example if a noxious
stimulation is performed after taking a placebo pill, the study subject no longer
believes in the effect of the placebo pill [29]. In our study, patients who
expected nausea apparently had an increased risk for nausea, in concordance with
findings regarding chemotherapy-induced nausea [32]. Thus, patients are either
capable of judging their own risk for nausea or the negative expectations per se
produce nausea. This finding implies that health care professionals might well
consider asking the patients about their expectations about experiencing nausea and
might consider the information to decide on appropriate antiemetic treatment.

Since nausea was prevalent in the standard care group and nausea may be associated
with a reduced quality of life [1], [33] treatment using verum or sham acupuncture may be valuable
and cost-effective since positive effects do occur. A crude calculation of the cost
for providing the median number of 11 verum or sham sessions lasting 30 minutes each
results in a mean cost per patient of $69 USD. Two patients (median) were
treated at the same time, meaning that one patient consumed three therapist
hours*. In comparison, the approximate costs of the recommended dose [6] of 8 mg of a
serotonin-receptor antagonists once per day during the radiotherapy period is
$98 USD**.

Emesis was measured using a well-established method [17]. The standard care cohort
rated emesis only once, covering the preceding week. Some patients in the standard
care cohort may, by forgetfulness, have underreported emesis, compared to the
acupuncture cohort, who rated emesis daily. The acupuncture cohort was compared with
a reference group, not to a third randomized arm. That design requires for a
thorough investigation of potential imbalance of confounding factors between groups,
as discussed above, but the design may have the benefit of avoiding the impact of
the data collection per se on reported emesis. Repeated measurement of emesis per se
may reduce (through the so called Hawthorne effect) or increase emesis experience
[34]. Young and
co-workers found that emesis questions per se increased self-reported occurrence of
nausea [34]. To pay
extra attention to emesis through daily data collection, without performing any
extra emesis-reducing treatment in this frail patient cohort, was therefore
evaluated as being unethical. We presented a cross sectional comparison at the time
when the mean radiotherapy dose was the same in the acupuncture and the standard
care cohorts. If we instead had observed another week of the radiotherapy period, it
would not have changed the conclusions of this study; the weekly proportion of
patients experiencing nausea was lower in the acupuncture cohort all radiotherapy
weeks (varied 22 to 44% as described previously [13]) compared to the standard care
cohort. The patients who were treated by verum or sham experienced close to
50% lower occurrence of emesis compared to the patients receiving standard
care. If the extra care caused the emesis reduction, this indicates that as long as
the best available antiemetic treatment is offered, patients who believe that
acupuncture has beneficial effects may be satisfied with treatment with verum
acupuncture or non-penetrating needles, either of which produces a moment of
relaxation and attention from the therapist. A next obvious step is to further study
what components in the acupuncture procedures are of importance for this
dramatically positive but as yet not fully understood effect, in an effort to make
possible the use of those components to further increase quality of care.

* A public hospital employing a physiotherapist for three hours spends $68
USD (408 SEK to provide the mean salary value for that service according to Swedish
Association of Registered Physiotherapists 2007, www.valuta.se, date 080404). Costs
for needles may be approximately $0.72 USD (24 needles consumed during 12
sessions, at six US cents according to prices at www.acuprime.com, date
101109).

** Consuming one tablet at a cost of 16.25 SEK (www.fass.se) during the mean value of
36 radiotherapy days in treatment costs $98 USD (based on cost in Sweden of
850 SEK www.valuta.se, date 101109).

Supporting Information

Acknowledgments

We are thankful to the participating patients, to Boel Lindberg and Ingrid Tillgren
for coordinating, to Marianne Frid, Annica Tomasson, Clary Skoglund, Eva Ahlner and
Lotta Robert for acupuncture treatments and to the health-care professionals at the
radiotherapy-departments for cooperation.